PROJECT SUMMARY Circadian rhythms are critical to the maintenance of good physical and mental health, and their disruption, such as that induced by night or rotating shiftwork, jet lag, or various pathological conditions, is known to negatively affect numerous health outcomes and an individual?s quality of life. While a variety of drugs, both medicinal and recreational, have been investigated for their impacts on biological rhythms, mostly with regard to the sleep/wake cycle, one class of drug that has not received much attention are the cannabinoids. This is a significant oversight, as recent data suggests that the endogenous cannabinoid system plays a significant role in regulating the master circadian clock located in the suprachiasmatic nucleus of the hypothalamus (SCN), thus making it likely that exogenous cannabinoids too would affect the clock. Unfortunately, little to nothing is known about how cannabinoids interact with the clock at the molecular, systems, or behavioral levels, which given recent changes to state laws that have resulted in a rise in the use of both medical and recreational marijuana, is a timely and important question that should be answered. The goals of this project are to examine how cannabinoids affect rhythmicity and to identify the neural substrates that mediate these effects, particularly the ability of the body to properly synchronize internal rhythms to external environmental cues. The proposed experiments are designed to test the central hypothesis that cannabinoid activity can alter the timing of behavioral circadian rhythms, and that this activity occurs through action on the SCN. The first aim of this study will be to determine the consequences of the loss of signaling through cannabinoid receptor 1 to the expression of behavioral circadian rhythms. The second aim will identify the molecular components of the cannabinoid system that are present in the SCN, and whether they are rhythmically expressed. The third and final aim will whether the lack of CB1 receptors in knockout mice have organizational effects on the brain that alter circadian clock function. With increased use of marijuana in the United States, it is critically important that we understand the biological mechanisms of the cannabinoid system to be able to evaluate potential impacts of cannabinoid use on human health. Evaluation of the contribution of cannabinoid signaling to circadian clock function will be an important step in this process.